Review article
Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications

https://doi.org/10.1016/S0939-6411(03)00161-9Get rights and content

Abstract

This review presents a critical analysis of covalently and ionically crosslinked chitosan hydrogels and related networks for medical or pharmaceutical applications. The structural basis of these hydrogels is discussed with reference to the specific chemical interactions, which dictate gel formation. The synthesis and chemistry of these hydrogels is discussed using specific pharmaceutical examples. Covalent crosslinking leads to formation of hydrogels with a permanent network structure, since irreversible chemical links are formed. This type of linkage allows absorption of water and/or bioactive compounds without dissolution and permits drug release by diffusion. pH-controlled drug delivery is made possible by the addition of another polymer. Ionically crosslinked hydrogels are generally considered as biocompatible and well-tolerated. Their non-permanent network is formed by reversible links. Ionically crosslinked chitosan hydrogels exhibit a higher swelling sensitivity to pH changes compared to covalently crosslinked chitosan hydrogels. This extends their potential application, since dissolution can occur in extreme acidic or basic pH conditions.

Introduction

Chitosan is a copolymer of β-(1→4)-linked 2-acetamido-2-deoxy-d-glucopyranose and 2-amino-2-deoxy-d-glucopyranose. This polycationic biopolymer is generally obtained by alkaline deacetylation from chitin, which is the main component of the exoskeleton of crustaceans, such as shrimps [1]. The main parameters influencing the characteristics of chitosan are its molecular weight (MW) and degree of deacetylation (DD), representing the proportion of deacetylated units. These parameters are determined by the conditions set during preparation. Moreover, they can be further modified. For example, the DD can be lowered by reacetylation [2] and MW can be lowered by acidic depolymerisation [3].

Chitosan is currently receiving a great deal of interest for medical and pharmaceutical applications. The main reasons for this increasing attention are certainly its interesting intrinsic properties. Indeed, chitosan is known for being biocompatible allowing its use in various medical applications such as topical ocular application [4], implantation [5] or injection [6]. Moreover, chitosan is metabolised by certain human enzymes, especially lysozyme, and is considered as biodegradable [7], [8]. In addition, it has been reported that chitosan acts as a penetration enhancer by opening epithelial tight-junctions [9], [10]. Due to its positive charges at physiological pH, chitosan is also bioadhesive, which increases retention at the site of application [11], [12]. Chitosan also promotes wound-healing [13], [14] and has bacteriostatic effects [15], [16]. Finally, chitosan is very abundant, and its production is of low cost and ecologically interesting [17]. In medical and pharmaceutical applications, chitosan is used as a component in hydrogels.

This review is focused on chitosan hydrogels intended for medical or pharmaceutical applications. There are several possible definitions of a hydrogel; we will use the one given by Peppas [18] who defined hydrogels as macromolecular networks swollen in water or biological fluids. Examples of networks related to hydrogels that correspond to this definition will also be introduced. Due to the various possible definitions of a hydrogel, different methods of classification are possible. Based on the definition given here, hydrogels are often divided into three classes depending on the nature of their network, namely entangled networks, covalently crosslinked networks and networks formed by secondary interactions. The latter class contains all the intermediary cases situated between the two other classes representing the extremes [19]. However, with respect to chitosan hydrogels, this classification is not entirely suitable. Certainly, there are no strict borders between these classes, but there is a continuum of various gels ranging from entangled chitosan hydrogels to covalently crosslinked chitosan hydrogels. Therefore, we suggest the following modified classification for chitosan hydrogels, i.e. the separation of chemical and physical hydrogels. Chemical hydrogels are formed by irreversible covalent links, as in covalently crosslinked chitosan hydrogels. Physical hydrogels are formed by various reversible links. These can be ionic interactions as in ionically crosslinked hydrogels and polyelectrolyte complexes (PEC), or secondary interactions as in chitosan/poly(vinyl alcohol) (PVA) complexed hydrogels, grafted chitosan hydrogels and entangled hydrogels. The latter are formed by solubilisation of chitosan in an acidic aqueous medium [4], [20], [21], which is the simplest way to prepare a chitosan hydrogel. Entangled chitosan hydrogels will not be discussed further in this review, as they are limited by their lack of mechanical strength and their tendency to dissolve. Moreover, they do not exhibit characteristics that allow drug delivery to be efficiently controlled—such as the modification of their properties in response to changes in their physicochemical environment, such as pH or temperature.

The present review is exclusively concerned with chitosan hydrogels formed by the addition of a crosslinker, namely covalently or ionically crosslinked hydrogels. A second review, entitled ‘Structure and interactions in chitosan hydrogels formed by complexation or aggregation for biomedical applications’ will discuss hydrogels formed by direct interaction between polymeric chains, without the addition of crosslinkers. They can be formed by complexation with another polymer, generally ionic, or by aggregation after chitosan grafting [22]. In crosslinked hydrogels, polymeric chains are interconnected by crosslinkers, leading to the formation of a 3D network (Fig. 1). Crosslinkers are molecules of MW much smaller than the MW of the chains between two consecutive crosslinks [23]. The properties of crosslinked hydrogels depend mainly on their crosslinking density, namely the ratio of moles of crosslinking agent to the moles of polymer repeating units [23]. Moreover, a critical number of crosslinks per chain is required to allow the formation of a network, such as that of a hydrogel [24]. Depending on the nature of the crosslinker, the main interactions forming the network are covalent or ionic bonds. The structures and interactions forming the covalently and ionically crosslinked hydrogels will be presented, their principles of formation and properties will be considered and examples of medical or pharmaceutical applications will be given. Their potential biocompatibility will be discussed, although some examples will refer to systems that are still in development, while others have already been tested in animals. To date, only one hydrogel presented in this review has been tested in humans. Consequently, their potential biocompatibility will sometimes be evaluated based on the intrinsic biocompatibility of their components.

Section snippets

Structure and interactions

Hydrogels based on covalently crosslinked chitosan can be divided into three types with respect to their structure: chitosan crosslinked with itself (Fig. 1a), hybrid polymer networks (HPN) (Fig. 1b) and semi- or full-interpenetrating polymer networks (IPN) (Fig. 1c). The simplest structure presented here is chitosan crosslinked with itself. As represented in Fig. 1a, crosslinking involves two structural units that may or may not belong to the same chitosan polymeric chain [25]. The final

Ionically crosslinked chitosan hydrogels

Most of the crosslinkers used to perform covalent crosslinking may induce toxicity if found in free traces before administration. A method to overcome this problem and to avoid a purification and verification step before administration is to prepare hydrogels by reversible ionic crosslinking. Chitosan is a polycationic polymer, well known for its chelating properties [93]. Therefore, reactions with negatively charged components, either ions or molecules, can lead to the formation of a network

Advantages and disadvantages of crosslinked chitosan hydrogels

Among the four types of chitosan hydrogels presented in the introduction, covalently crosslinked hydrogels are the only systems characterised by a permanent network, due to their irreversible chemical links. Therefore, they exhibit good mechanical properties and can overcome dissolution, even in extreme pH conditions, while the other types of hydrogels are more labile. To obtain hydrogels with these interesting characteristics, the use of covalent crosslinkers is necessary. However, most of the

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    Dedicated to the memory of Joachim M. Mayer.

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